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B cells constitute a diverse and adaptable immune cell population with functions that can vary according to the environment and circumstances. The involvement of B cells in pregnancy, as well as the associated molecular pathways, has yet to be investigated. This review consolidates current knowledge on B cell activities and regulation during pregnancy, with a particular focus on the roles of various B cell subsets and the effects of B cell-derived factors on pregnancy outcomes. Moreover, the review examines the significance of B cell-associated autoantibodies, cytokines, and signaling pathways in relation to pregnancy complications such as pregnancy loss, preeclampsia, and preterm birth.

Background The maternal immune system needs to tolerate the semi-allogeneic fetus in pregnancy. The adaptation occurs locally at the maternal–fetal interface as well as systemically through the maternal circulation. Failure to tolerate the paternal antigens may result in pregnancy complications, such as pregnancy loss and pre-eclampsia. However, the mechanism that regulates maternal immune tolerance, especially at the systemic level, is still an enigma. Here we report that the first-trimester placenta-derived exosomes (pEXOs) contribute to maternal immune tolerance by reprogramming the circulating monocytes. Results pEXOs predominantly target monocytes and pEXO-educated monocytes exhibit an immunosuppressive phenotype as demonstrated by reduced expression of marker genes for monocyte activation, T-cell activation and antigen-process/presentation at the transcriptomic level. They also have a greater propensity towards M2 polarization when compared to the monocytes without pEXO treatment. The inclusion of pEXOs in a monocyte-T-cell coculture model significantly reduces proliferation of the T helper cells and cytotoxic T cells and elevates the expansion of regulatory T cells. By integrating the microRNAome of pEXO and the transcriptomes of pEXO-educated monocytes as well as various immune cell functional assays, we demonstrate that the pEXO-derived microRNA miR-29a-3p promotes the expression of programmed cell death ligand-1, a well-known surface receptor that suppresses the adaptive immune system, by down-regulation of phosphatase and tensin homolog in monocytes. Conclusions This is the first report to show how human pEXO directly regulates monocyte functions and its molecular mechanism during early pregnancy. The results uncover the importance of pEXO in regulating the maternal systemic immune response during early pregnancy by reprogramming circulating monocytes. The study provides the basis for understanding the regulation of maternal immune tolerance to the fetal allograft. Graphical Abstract

Background Early-onset pre-eclampsia (ePE) is a severe pregnancy complication characterized by dysregulated trophoblast functions and impaired placentation during early pregnancy, leading to substantial maternal and fetal morbidity. While circumstantial evidence indicates defective secretion from endometrial glands impairs placental development, direct evidence linking maternal glandular dysfunction to ePE pathogenesis remains elusive. Methods We established endometrial glandular organoids from women with ePE and healthy pregnancies, analyzing their secretomes by iTRAQ-based proteomics, RNAseq, and spatial transcriptomics. Functional effects of organoid secretomes on trophoblasts were examined in vitro. An endometrial-specific apolipoprotein D (APOD) knock-in mouse model was studied in vivo. APOD levels in first-trimester serum samples from women who later developed ePE were compared to healthy pregnancies. Results Secretomes from ePE derived endometrial organoids impeded spiral artery remodeling. Multiomic analyses revealed increased APOD production in both ePE organoids and decidual tissues. APOD overexpression disrupted trophoblast functions and endothelial vascular remodeling in vitro, and recapitulated ePE phenotypes in an APOD knock-in mouse model through PI3K/Akt-mediated placental ferroptosis and potential ER stress induction. Ferroptosis inhibition with Fer-1 rescued placental defects and PE symptoms in APOD knock-in mice. Elevated APOD levels in first-trimester serum samples from women who later developed ePE suggest its potential as an early biomarker. Conclusion This study provides the first direct evidence linking dysregulated endometrial gland function to defective placentation and ePE. APOD was identified as a crucial endometrial gland-secreted factor contributing to ePE, suggesting its potential as an early biomarker and therapeutic target.

Adult endometrial glands undergo cyclic regeneration and development during the menstrual cycle. Their secretions are vital for endometrial functions and early pregnancy, yet the mechanisms controlling gland development are not well understood. Although various 3D endometrial models exist, none fully replicate human gland development in vitro. This study establishes a robust 3D endometrial assembloid model by integrating human endometrial organoids (EOs) and human endometrial stromal cells (HESCs), successfully replicating tubular gland formation and illustrating essential stromal‐epithelial interactions. Transcriptomic analyses identify Wnt Family Member 7B (WNT7B) as an intrinsic inhibitor of gland formation and development, regulated extrinsically by transforming growth factor beta‐1 (TGFβ1) signaling through vitamin D receptor (VDR) interactions between EOs and HESCs. Endometrium‐specific WNT7B knockout mice exhibit enhanced gland development further supports WNT7B's inhibitory role in endometrial gland development. Estradiol facilitates tubular gland formation by suppressing WNT7B expression in vitro, which is confirmed in estradiol‐stimulated mouse models and clinical samples from women undergoing ovarian stimulation for in vitro fertilization. These findings elucidate the central roles of estradiol‐WNT7B signaling and stromal‐derived TGFβ1‐VDR crosstalk in endometrial gland development, providing a foundation for improved 3D endometrial models and identifying therapeutic targets for gland‐related disorders like endometriosis, infertility, and endometrial hyperplasia. This study developed a 3D endometrial assembloid model to study how uterine glands form and develop. They discovered key interactions between different cell types and identified WNT7B as a regulator controlled by estradiol‐mediated TGFβ1‐VDR interaction. These findings confirmed in in vitro, animal and clinical studies, provide a foundation for advanced 3D models and potential treatments targeting disorders related to uterine glands.

Background and Objectives: The usual recommended intake of vitamin D for healthy infants is 400 international unit (IU) daily. However, a high dose of vitamin D at 2000-3000 IU daily is needed for those with vitamin D deficiency (VDD). This study aimed to assess the natural history of a group of healthy infants with VDD and the associated factors for persistent VDD. Methods and Study Design: Healthy infants detected to have VDD (25OHD <25 nmol/L) in a population study were followed, and their demographics and clinical data were collected. Results: One hundred and thirty-one subjects (boys equivalent 66%) were included. Their first serum 25OHD was taken at a median age of 87.5 days. None were treated with high-dose vitamin D supplements, but some have been given vitamin D at 400 IU daily. They were assessed again at the median age of 252.5 days when 15 remained to have VDD and 26 were in the insufficient range (25 - 49.9nmol/L). All persistent VDD children were on exclusive breastfeeding. Exclusive breastfeeding and no vitamin D supplementation were significant risk factors for persistent vitamin D insufficiency (<50nmol/L). Conclusions: Persistent VDD is common among infants exclusively breastfeeding and those who did not receive vitamin D supplementation.

The management of viral hepatitis in the setting of pregnancy requires special consideration. There are five liver-specific viruses (hepatitis A, B, C, D, E), each with unique epidemiology, tendency to chronicity, risk of liver complications and response to antiviral therapies. In the setting of pregnancy, the liver health of the mother, the influence of pregnancy on the clinical course of the viral infection and the effect of the virus or liver disease on the developing infant must be considered. Although all hepatitis viruses can harm the mother and the child, the greatest risk to maternal health and subsequently the fetus is seen with acute hepatitis A virus or hepatitis E virus infection during pregnancy. By contrast, the primary risks for hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus are related to the severity of the underlying liver disease in the mother and the risk of mother-to-child transmission (MTCT) for HBV and HCV. The prevention of MTCT is key to reducing the global burden of chronic viral hepatitis, and prevention strategies must take into consideration local health-care and socioeconomic challenges. This Review presents the epidemiology of acute and chronic viral hepatitis infection in pregnancy, the effect of pregnancy on the course of viral infection and, conversely, the influence of the viral infection on maternal and infant outcomes, including MTCT. The management of viral hepatitis in the setting of pregnancy requires special consideration. This Review examines each hepatitis virus individually to address the effect of pregnancy on the natural history of infection and how the viral infections influence maternal and infant outcomes, including mother-to-child transmission. Key points Acute hepatitis A virus (HAV) infection during pregnancy might increase the rates of adverse pregnancy outcomes; cases leading to fetal liver injury and mother-to-child transmission (MTCT) of HAV have been reported. Pregnant women with chronic hepatitis B virus (HBV) infection might have an increased risk of preterm delivery and gestational diabetes. There is risk of MTCT of HBV, especially in mothers with high levels of HBV DNA, but this risk is reduced with the use of maternal antiviral therapy and prompt administration of infant immunoprophylaxis. Pregnant women with chronic hepatitis C virus (HCV) infection have increased rates of adverse pregnancy outcomes; MTCT occurs in 5% and is linked with invasive fetal monitoring and prolonged rupture of membranes. Risks related to underlying cirrhosis can be more frequent in pregnant women with hepatitis D virus (HDV) infection; MTCT of HDV is rare and management is the same as HBV monoinfection. Acute hepatitis E virus (HEV) infection in pregnancy is associated with an increased risk of maternal death and infant mortality, including higher rates of preterm delivery and stillbirths; MTCT of HEV can occur.

Integrating telehealth in an obstetric care model is important to prepare for possible infection outbreaks that require social distancing and limit in-person consultations. To ensure the successful implementation of obstetric telehealth in Hong Kong, it is essential to understand and address pregnant women’s concerns. This study aimed to assess pregnant women’s attitudes, concerns, and perceptions regarding telehealth obstetric clinic services in Hong Kong. We conducted a prospective cross-sectional questionnaire study at Queen Mary Hospital between November 2021 and August 2022. Utilizing a 5-point rating scale, the questionnaire aimed to capture pregnant women’s preferences, expectations, feasibility perceptions, and privacy concerns related to telehealth clinic services. We used statistical analyses, including chi-square tests and multinomial logistic regression, to compare questionnaire responses and investigate the association between advancing gestation and attitudes toward telehealth clinics. The study included 664 participants distributed across different pregnancy stages: 269 (40.5%) before 18 gestational weeks, 198 (29.8%) between 24 and 31 weeks, and 197 (29.7%) after delivery. Among them, 49.8% (329/664) favored face-to-face consultations over telehealth clinics, and only 7.3% (48/664) believed the opposite. Additionally, 24.2% (161/664) agreed that telehealth clinics should be launched for obstetric services. However, the overall preference for telehealth clinics was <20% for routine prenatal checkups (81/664, 12.2%) and addressing pregnancy-related concerns, such as vaginal bleeding (76/664, 11.5%), vaginal discharge (128/664, 19.4%), reduced fetal movement (64/664, 9.7%), uterine contractions (62/664, 9.4%), and suspected leakage of amniotic fluid (54/664, 8.2%). Conversely, 76.4% (507/664) preferred telehealth clinics to in-person visits for prenatal education talks, prenatal and postpartum exercise, and addressing breastfeeding problems. Participants were more comfortable with telehealth clinic tasks for tasks like explaining pregnancy exam results (418/664, 63.1%), self-administering urinary dipsticks at home (373/664, 56.4%), medical history-taking (341/664, 51.5%), and self-monitoring blood pressure using an electronic machine (282/664, 42.8%). %). During the postpartum period, compared to before 18 weeks of gestation, significantly more participants agreed that telehealth clinics could be an option for assessing physical symptoms such as vaginal bleeding (aOR 2.105, 95% CI 1.448-3.059), reduced fetal movement (aOR 1.575, 95% CI 1.058-2.345), uterine contractions (aOR 2.906, 95% CI 1.945-4.342), suspected leakage of amniotic fluid (aOR 2.609, 95% CI 1.721-3.954), fever (aOR 1.526, 95% CI 1.109-2.100), and flu-like symptoms (aOR 1.412, 95% CI 1.030-1.936). They were also more confident with measuring the symphysis-fundal height, arranging further investigations, and making diagnoses with the doctor via the telehealth clinic. The main perceived public health advantage of telehealth clinics was the shorter traveling and waiting time (526/664, 79.2%), while the main concern was legal issues from wrong diagnosis and treatment (511/664, 77.4%). Face-to-face consultation remained the preferred mode of consultation among the participants. However, telehealth clinics could be an alternative for services that do not require physical examination or contact. An increased acceptance of and confidence in telehealth was found with advancing gestation and after delivery. Enforcing stricter laws and guidelines could facilitate the implementation of telehealth clinics and increase confidence in their use among pregnant women for obstetric care.

Purpose Chronic hepatitis B virus (HBV) infection remains endemic and continues to cause significant morbidity and mortality. It is a global health issue and the World Health Organization aims to eradicate HBV by 2030. Since vertical transmission accounts for the majority of chronic HBV infection, pregnancy offers an excellent opportunity to achieve complete HBV eradication by providing effective immunization of the offspring. Methods We reviewed recent publications identified from PubMed database using a combination of the relevant keywords for HBV, pregnancy, vertical transmission, immunoprophylaxis failure and antiviral treatment. Results We summarized the evidence of factors associated with, and measures to reduce and prevent maternal to child transmission, including the use of antiviral treatment during pregnancy to prevent immunoprophylaxis failure. Evidence suggested that highly viremia mother can be offered antenatal antiviral treatment to prevent immunoprophylaxis failure. We elaborated the viral load threshold to start maternal antiviral treatment and the importance of timely neonatal vaccination. A clinical algorithm to manage HBV carriers during pregnancy was proposed. Conclusion Eradication of HBV is achievable with optimal management of HBV carriers, especially during pregnancy by interruption of vertical transmission. Routine antenatal screening and neonatal immunoprophylaxis remain the key measures to reduce the global HBV burden, and additional antenatal antiviral treatment could further minimize the chance of persistent infection in newborns.

Medulla Tetrapanacis (MT) is a commonly used herb to promote lactation and manage mastitis in lactating mothers. However, its anti-inflammatory and anti-bacterial effects are currently unknown. We hypothesized that MT water extract possesses anti-inflammatory and anti-bacterial effects by modulating macrophage polarization to reduce the release of inflammatory mediators and phagocytosis via inactivation of MAPKs pathways. The chemical composition of the MT water extract was analyzed by UPLC-Orbitrap-mass spectrometry. The anti-inflammatory and anti-bacterial properties of the MT water extract were examined using LPS-stimulated inflammation and Staphylococcus aureus infection model in RAW 264.7 cells, respectively. The underlying mechanism of action of the MT water extract was also investigated. We identified eight compounds by UPLC-Orbitrap-mass spectrometry that are abundant within the MT water extract. MT water extract significantly suppressed LPS-induced nitric oxide, TNF-α and IL-6 secretion in RAW 264.7 cells which was accompanied by the promotion of macrophage polarization from pro-inflammatory towards anti-inflammatory phenotypes. MT water extract significantly suppressed the LPS-induced MAPK activation. Finally, MT water extract decreased the phagocytic capacity of the RAW 264.7 cells against S. aureus infection. MT water extract could suppress LPS-induced inflammation by promoting macrophages towards an anti-inflammatory phenotype. In addition, MT also inhibited the growth of S. aureus . Graphical abstract